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17 February 2011
Table of contents
1. Abstract
2. Current Developments of Major Histocompatibility Complexes and their Importance in Transplantation
3. Introduction
4. Processing of antigens by MHCs
5. Functions of MHC’s
6. The Role of MHC in Transplantation
6.1Ways of increasing the survival of a transplanted organ in a recipient
6.2 Development in the Transplantation of Grafts
7. Conclusion
8. References
- 1. Abstract
Major Histocompatibility Complexes are essential during the process of transplantation since they help to predict the outcome of a transplant, who is a qualified donor and recipient for a certain graft. They are also essential in the choosing of mates and communal nurturing in viviparous animals. Further they help us to trace our origins but their main work is responding to antigens and assisting in inducing immune responses. They are of two kinds that function differently and are degenerate thus appearing as multiple alleles. Improvement have also been done on the surgical transplantation processes and techniques to prevent graft rejection and enhance the survival of both the individual and the transplant, such include the immune suppression medication with less side effects, the use of induction methods and abdominal transplantations other than surgery have been introduced, using of artificial organs to curb the problem of few donors and incompatibility of MHCs have been introduced. Easy compatibility tests involving just a blood test have also been introduced to save time for determining the right donor. This has made easier this process and improved the possibility of success.
- 2. Current Developments of Major Histocompatibility Complexes and their Importance in Transplantation
- 3. Introduction
Major Histocompatibility Complex (MHC) is a group of a gene family found in majority of vertebrates and encodes molecules of MHC. They have been found to be very significant in autoimmunity thus play great roles in the immune system. Their work is to present remains of processed proteins on the surface of the cell in the form of short sequences of proteins which are peptides. These are effective against pathogens since their work is to survey with the help of other immune cells usually the Natural Killer Cells (NKC’s) and the T cells. Once these MHC: peptides bind on the pathogens they activate the immune cells to mount up a response against the pathogens. The MHC defend the body against a diverse number of microbes thus their peptides much also be varied, they are thus referred to us degenerate. MHC achieves this due to their nature of being polymorphic, their loci are also polygonal and they have got many alleles. They also have all their genes being co dominant while majority of them are expressed concurrently (Aderem, Alan; Underhill & David 1999, 593-623). They are of two kinds: class I that is found mainly in cells with a nucleus and are expressed on cytotoxic T cells and class II found in Antigen presenting cells (APC’s) such as macrophages, dendritic and B cells. These APCs take in any pathogen, develop them to produce pathogens within a phagosome then they present these waste to helper T cells that stimulate immune responses fro other cells (Afzali, B et al, 2008, 438-494). Immune responses and elimination of pathogens occur by phagocytosis and apoptosis which is programmed cell death. MHC III is also present but is not directly involved in immune response but encodes other immune components such as Tumor Necrosis Factor α and cytokines. MHCs are also significant in determining post transplant reaction and also the changes that have occurred since evolution. It is with this realization that this study is focused to validate the role of MHCs in transplantation and developments that are being done to modify the transplantation process.
- 4. Processing of antigens by MHCs
MHC’s by displaying antigens on the cell surface of the host alerts the immune system of the presence of an antigen. These antigens may be at times nonself not from the host or self from the host. Phagocytic macrophages and dendritic cells engulf antigens with already formed endosomes then combine with lysosomes to cause destruction. The digested and damaged particles are laden on MHC II and taken to the cell surface since they are APCs. Nucleus containing cells also present peptides on their cytosol especially the class I. This is particularly important in eliminating infections of bacterium, viruses and pathogens causing lesions.
(http://www.microrao.com/micronotes/mhc.pdf) 2006, 2 0f 5, Figure 1: How Major Histocompatible Complex Process Antigens
- 5. Functions of MHC’s
The work of MHC’s is to present a complex of antigens and peptides to T lymphocytes that help in mounting up an immune response to destroy the antigenic pathogens. Their corresponding pathways are however dissimilar thus the antigen processing is different. In the case of MHC I the composition of protein-MHC composite is polymorphic with β2 microglobulin and α chain with the peptide bound to α chain unlike the class II that has α and β chains bound to the peptide as shown in the above diagram. Class I mainly responds to CD8+ cells and bind to proteins originating from the cytoplasm while class II responds to CD4+ cells and bind proteins in lysosomes and endosomes. The loading of MHC for class I is via the endoplasminc recticulum while in II a special vesicle is used. According to James et al (2011, 1 of 1) the major function of MHC is immune recognition, social signaling and mate choice. In this case mates that have different MHC are favored as mating partners. Further MHC are determinants during communal nurturing of young ones in that mothers of the same MHCs will take care of the young ones without any bias. This shows negative selection in the choosing of partners but favored selection in the taking care of young ones dependent on the difference and similarity in MHCs respectively (Campbell & Trowdsdale, 1993, 349-352). They signal relatedness, genetic compatibility and quality among other immune functions. These complexes however have a major role in histocompatiblity and immune regulations. In anthropology HLAs are used to distinguish between populations and show their interrelationships. This has been used to study groups such as the Caucasoid and Chinese. They have also been used in paternity tests where by if a parent has closely related HLA with parent then it can be proven that he is the parent but if the haplotype are not close then there is no possibility of parenthood. MHC’s have also been vital in forensic science, transfusion of fluid from one individual to another and disease association with certain groups of MHC being more prone to a specific disease than others (Lechler et al, 1990, 83-88).
- 6. The Role of MHC in Transplantation
MHC’s have also been identified particularly in their role in graft rejection from genetically different strains of mice and other experimental animals. In humans they are referred to us human leukocyte antigens (HLA) as according to (Abbas & Lichtman, 2009). Each human has six alleles of class I and between 6 and 8 alleles of class II. Those for class I are A, B, C and their progenitors while MHC II DP and DQ which can have one or two progenitors and DR with its progenitor among other small combinations. Each of these genes has a multi locus with many alleles thus each individual in most cases has alleles different from the other with exception of identical twins. Each of these MHC is susceptible to transplant rejection with the one that show less polymorphism such as HLA-C and HLA-DP showing less possibility of rejection.
During the case of organ or transplant of stem cells MHC function as antigens and can start an immune reaction at the receptors of the recipient of the graft thus aggravate a graft rejection. Their presence in cells causes a very powerful immune reaction of those known thus individual response towards another’s MHCs are conspicuous. In their maturation stages the T lymphocytes are selected based on their T cell receptors (TCR) ability to recognize the complexes thus principle T cells should not mount up a response against their complexes. This means that during a transplant a response is initiated since the donor’s T cells are different from those of the recipient. In this case a cross reaction occur and the lymphocytes of the receptor perceive the cells of the transplanted organ in the self to be foreign thus mount up a immune reaction causing an incursion of the organ. This process where T cells recognize foreign MHC to be self antigens is known as allorecognition thus resulting to two types of rejection (Gould et al, 1999, 77-82)
The first is the Hyperacute rejection that which occurs when an individual already formed antibodies generated through a prior blood transfusion since it contains donor lymphocytes that have MHC’s, pregnancy and a previous transplant from the same individual. This occurs before the transplantation. The other form of rejection is the chronic and acute rejections. These occur due to formation of HLA antibodies in the recipient in opposition to the cells of the endothelium of the grafted tissue. In both cases they are concurrent responses that cause the growth of tumors in the organ transplanted causing immediate loss of function in hyperacute rejection and progressive dysfunction in the case of chronic and acute rejections (George et al.1990, 209-11). Tests for cross reactions between the recipient and donor of both cells and organs should be done to recognize any source of preformed MHC’s avoiding hyperacute rejection which is fatal. The compatibility of HLA-B, -DR, and –B alleles is normally checked since the lower the compatibilities the lower the ability of the graft to resist rejection thus low chances of survival. Total compatibility has also been evident in identical twins though optimization can be done now days. HLA is thus very important pre-transplant histocompatibility and in immunology of transplants and the associated tests. Transplants with cadaveric patients have proved more prone to graft rejection than those of donors who are alive. Reactions of the host versus graft are the resultant of rejection and the key obstacle in transplantation of organs. Rejection varies based on the nature of the antigens in the graft and the immune status of both the donor and the recipient. Another way in which the MHC can induce graft rejection is through the innate system where peptides on the endothelial of the cells can kill the NKCs and the CD8+ cells causing the lack of immunity thus the graft is attacked. Further there is a possibility of poor organ transplant outcome and lack of sensitization if they are many polymorphic antigens within the graft or in the recipient’s immune system. Antibody mediated rejection can also occur if one was administered with an anti lymphocyte therapy after transplantation and results are similar to those of hyperacute rejection. Transplant rejection due to MHC or HLA incompatibility has resulted to what is known as graft versus host disease (Rogers et al, 1998, 206-208) causing complications on consecutive transplants. This is a complication of the bone marrow recognizing the cells from the recipient as foreign and mounting up immune responses.
6.1 Ways of increasing the survival of a transplanted organ in a recipient
Many successful grafts of the cornea, kidney and heart have been done in practice but the danger of rejection is still glaring and it is with this realization that for each transplant that is undertaken, safety measures to prevent rejection have to be accompanied. Donor selection is the most essential in transfer. According to Rogers et al (1998, 206-208) about 95-100 % identical MHC of donor and recipient will outright give you a successful transplant while for allografts and xenografts the possibility of rejection is very high. Recipients must also be screened for anti HLAs that are donor specific and to improve survival, blood containing similar HLA as those of the graft should be transfused every 1-2 weeks on post transplantation. Immunosuppression therapy is crucial as this will help in avoiding infections; block the synthesis of cytokines particularly IL-2 that helps in mounting and inducing an immune response and also avoid allorecognition. For bone marrow transplants the donor and the recipient should be MHC II compatible and the use of monoclonal antibodies is essential to prevent tumourigenesis. Not taking of these measures results to MHC related diseases such as celiac disease and insulin dependent diabetes mellitus (George et al, 1995, 209-11).
6.2 Development in the Transplantation of Grafts
These methods will help to improve the survival since the methods above are quite effective but only for a short while. These new methods are however specific to a certain kind of transplantation whether it’s for a certain organ of a kind of a cell but in both cases results to repercussions such as cancer and infections due to weak immune system. Standard immunosuppressive methods have been improved and include an initial baseline therapy to curb rejection followed by a therapy that is short lived with methlyprednisolone in high doses to further prevent rejection. Administration of antithymocyte and antilymphocyte globulins together with polyclonal antiserum and monoclonal antibodies is done to boost the immune system. These are very important during prophylaxis and acute rejection but they have a lot of variability and have non specific targeting of the body’s entire B cells thus administered through the central venous contact. Another improvement is the use of aspiration cytology method using a fine needle especially for kidney transplant. This must be done aseptically and can also use a spinal needle with a gauge where an RPMI-1640 culture medium is used together with the needle. The use of ultra sound as a guide to the progress of the transplantation can be done. Patients are then treated with Azothioprine and cyclosporine to prevent activation of IL-2 that cause acute rejection (Zhang et al, 1995, 103-9).
Induction protocols have also been introduced to prevent graft rejection and involve the use of FK 506 and cyclosporine recurrently. According to Zhang et al (1995, 103-9) and Brian and Stephen (2010, 1 of 1) microsurgical techniques that involve the transplantation of left kidney with anastomoses of end to side donor kidney vein to the donor renal vena cava and from the cuff of the aorta of the donor to the recipient has been done, then a reconstruction of the recipient’s urinary tract using parts of the donor has guaranteed 90% success of the graft transplant. It has opened field of study of immunological reactions of the kidney and how to control and prevent them.
Hair transplant procedures have also improved with the introduction of Cole Isolation Technique (CIT). This method is effective since it does not leave a linear scar at the back of your head. In this case natural hairs are extracted and transplanted to thinning regions of the recipients without further procedures. It is a very fast procedure and by far the most effective measure to treat hair loss. Anew procedure has also been developed to improve heart transplant where a central suture ligation of the abdominal aorta of the recipient and anastomosis with a donor’s heart aorta in the infrarenal portion of the recipient abdominal aorta is done (Hong et al, 2007, 12-5). In allografts and isografts it has proved to be successful and has low incidence of thrombosis and arteriosclerosis. In the transplantation of the pancreas a new method duodenoduodenostomy applies the mechanism of draining the secretions of the digestive system once the pancreas is in position behind the right colon. Merits of this technique are its ease in endoscopy evaluation of the duodenum of the donor. At times allograft pancreatectomy is required and reconstructive surgery can be done (Boggi et al, 2010, 102-111). In the transplantation of the jejuna suture between the hypopharynx and the trachea has been improved to be done isoperistaltically. Revascularization of the jejunum accompanied with anastomoses is done by the vessels of the cervix. Laryngectomy due to carcinoma has been done to replace the entire larynx and no thrombosis has been experienced thus a successful method to transplant both the jejunum and the larynx important in the production of voice. In all these cases the consideration of the compatibility of the HLAs and blood group is essential. Recently technologies of genetic expression testing have been simplified to just a blood test. One such test is the AlloMap Molecular Expression Testing thus helping to predict the outcome of a transplant prior the process depending on the MHCs (Aderem, Alan; Underhill & David 1999, 593-623). Currently the search for immunosuppressants that do not have fatal side effects such as infections and cancer is being researched on. The use of artificial hearts fitted with a cardiac pacemaker and artificial kidneys have also been introduced due to the shortage number of both cadaveric and live donors and due to the incompatibilities of the MHCs.
- 7. Conclusion
MHCs are important in surgical transplantation and in the immune system due to their ability to cause immune responses once there is an antigen, they are essential in allorecognition especially in allografts and xenografts. The compatibility between a donor and a recipient of a graft determines how much successful the transplantation will be. Other than immune system they affect the selection of mates and evolution of organisms. Improvements are currently underway to improve the surgical transplantations process reducing rejection of organs by ensuring the right immunosuppressive medication, introducing improved methods of different organ transplants that incorporate suturing of parts of the donor and recipients, reconstructive surgeries for organs of different size of donor and recipient and use of artificial organs among others. This is anticipated to improve the survival of the graft and the success of transplants.
References
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Brian J. and Stephen I. , The New England Journal of Medicine: Mechanisms of Disease in Rejection of the Kidney Allograft (2010) Volume 16, issue 2. Department of Surgery and Medicine, University of Western Ontario, London, Canada
Boggi, Ugoa, Amorese, Gabriella, Marchetti and Piero. A new method of surgical voice rehabilitation: microsurgical jejunum transplantation. (1986) Volume 18 issue 5, Germany
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(http://www.microrao.com/micronotes/mhc.pdf) 2006, 2 0f 5, Figure 1: How Major Histocompatible Complex Process Antigens.
James S. , Adam C., Nelson, Jason L., Kubinak and Wayne K. Social communication via MHC signaling: The scent of self, familial self and non-self Volume 2, Issue 1 (2011).
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Zhang, Z. , Schlachta, C. , Duff, J. , Stiller, C. , Grant, D. and Zhong, R. Improved techniques for kidney transplantation in mice. (2007) Volume 22, Korean Academy of Medical Sciences
